Leptin signaling in POMC neurons regulates plasma leptin levels and is critical to mediate hypothalamic-pituitary-adrenal axis activation during fasting.

The reduction in plasma leptin levels is crucial for the brain to perceive negative energy balance and activate adaptive responses, including activating corticotrophin-releasing factor neurons in the paraventricular nucleus of the hypothalamus (CRF). Notably, leptin receptor (Lepr) expression is rare in the PVN, and there are no reports of Lepr colocalization with CRF, suggesting that the effects of leptin on the hypothalamic-pituitary-adrenal (HPA) axis are mediated by indirect pathways. Since Lepr is abundantly expressed in agouti-related peptide (AgRP) and proopiomelanocortin (POMC) neurons in the ARC, we investigated the effects of deleting Lepr in these neurons on HPA axis activity during fasting and leptin treatment. Deletion of Lepr in AgRP neurons did not affect fasting-induced activation of ARC neurons or CRF neurons, nor did it impact corticosterone secretion. In these animals, leptin treatment remained effective in reducing HPA axis activity. Interestingly, animals with Lepr deletion in POMC neurons did not exhibit increased plasma corticosterone during fasting. This response was associated with unchanged plasma leptin, which may have contributed to the lack of responsiveness of non-POMC neurons and the absence of an increase in AgRP immunoreactivity in the ARC, ultimately resulting in no change in CRF neuronal activity. Although POMC neurons project to the CRF and can stimulate corticosterone secretion, this pathway appears unengaged during fasting. Our findings suggest that changes in leptin signaling in AgRP neurons do not affect the activation or suppression of HPA activity in response to fasting or leptin. In contrast, leptin signaling to POMC neurons appears to be essential for HPA activation and could be part of the array of endocrine responses associated with the decline in leptin levels during negative energy balance.